The radiopharmaceutical reagents of this invention, a class of tin-117m radiopharmaceuticals are therapeutic agents (that also incorporate gamma-emission) that localize predominantly in bone after intravenous injection. Images reflecting bone structure or function can also be obtained by a scintillation camera that detects the distribution of ionizing radiation emitted by the radioactive tin-117m agent.
Radiochemical reagents, by virtue of their radioactive emission, have become a most useful diagnostic and therapeutic tool. Some of these reagents incorporate a gamma-emitting nuclide and localize in a specific organ or bone after intravenous injection. Images reflecting the organ or bone can then be obtained by means of a scintillation camera that detects the distribution of ionizing radiation emitted by the radioactive reagent. The principal radioactive isotope used in diagnostic procedures is technetium-99m. Other clinically important diagnostic isotopes are thallium-201, gallium-67, and iodine-123. All the above are cyclotron-produced. Examples of therapeutic reagents which localize in pathologic tissue include iodine-131 and phosphorus-32, both reactor-produced.
In order to be an effective radioactive drugxe2x80x94whether for therapeutic or diagnostic usexe2x80x94the reagent must combine four elements: low toxicity, specific biodistribution, low background radiation (non-target) dose, and suitable therapeutic/diagnostic radionuclidic emissions. For example, 99mtechnetium combines with methylene diphosphonate (MDP) to form 99mTc-MDP, which localizes in the skeleton in general and in areas of hyperactive bone metabolism in particular. Biodistribution of this agent combines rapid, high concentration by target tissue and low uptake by surrounding tissue with rapid blood clearance and urinary excretion of the non-specifically localized radioactive drug. Thus, the amount of localized reagent to resolve the image on scintillation cameras is obtained with minimal radiation dose to the patient.
U.S. Pat. No. 4,533,541 to Srivastava, et al. discloses tin-117m radiopharmaceuticals as therapeutic and diagnostic agents that localize in bone after intravenous injection in mammals. The preferred chelates are phosphonate compounds such as pyrophosphate (PYP), methylene diphosphonate (MDP), ethylidenehydroxydisodium phosphonate (EHDP) and diethylene-triamine pentaacetic acid (DTPA).
U.S. Pat. No. 4,636,380 to Wong discloses a method of preparing nonradioactive stannous citrate for use as complexing agent for 111InCl3 to form bimetallic In(Sn) citrate which when added to 111InCl3 provides a covalently bonded radionuclide to a protein ligand.
Tin-117m exhibits radionuclidic properties acceptable for clinical and therapeutic use such as a half-life of 14 days, a gamma-emission of 158 keV photons, 87%, and the emission (total per decay) abundance of low energy Auger and conversion electrons. A short radioisotopic half-life is necessary to minimize patient exposure, but cannot be so short as to preclude commercial processing and transport. In addition, a useful radioisotope must yield gamma rays in reasonable abundance that can be imaged with currently available cameras. Internal scatter and absorption of low energy gamma emission and sensitivity and resolution constraints imposed by the collimators and electronics of current scintillation cameras limit useful isotopic emission from 50-60 keV to approximately 350 keV.
It has been found, however, that when using Tc-99m MDP the ratios of radioactivity concentration in bone versus other major tissues such as muscle, spleen liver, kidney and blood are high but not absolute. As a result Tc-99m will likely be found in the body in other organs in addition to sick organs.
Accordingly, it is an object of the present invention to provide radioactive chelates of tin-117m which are easy to prepare, have chemical and biological properties superior to other bone localizing pharmaceuticals, can be used for therapy of bone cancer and other bone disorders, and have a gamma emitting component that can be used for imaging biodistribution and for calculating dosimetry prior to initiating high-dose therapeutic administrations. It is another object of the present invention to provide therapeutic radiopharmaceuticals which have high bone uptake and as a result localize almost exclusively in skeletal tissue and exhibit low accumulation in other organs.
The present invention, which addresses the needs of the prior art, provides radiopharmaceutical compositions which includes 117mSn labeled stannic (Sn4+) chelates. The chelates are polyhydroxycarboxylates selected from the group consisting of oxalates, tartrates, citrates, malonates, gluconates, glucoheptonates and the like. Mixtures of the foregoing polyhydroxycarboxylates are also contemplated.
The present invention also provides a method of making 117mSn labeled stannic (Sn4+) polyhydroxycarboxylate. The method includes reacting 117mSnCl2 with a polyhydroxycarboxyclic acid followed by oxidizing the product of the first step with an oxidizing agent. Useful oxidizing agents include hydrogen peroxide and others that are compatible with the physiological system. An effective amount of tin-117m stannic polycarboxylate can be administered to localize in bone for scintigraphical analysis. The invention thus provides a method for radiopharmaceutical skeletal imaging which includes administering intravenously tin-117m labeled stannic polycarboxylate and detecting the radioactivity by applicable detection techniques. Methods for treatment of pain resulting from metastatic bone involvement including administering an effective amount of tin-117m labeled stannic polycarboxylate to a mammal are also provided by this invention. In this specification, bone involvement refers to the metastatic spread of cancer to bone. This invention also provides a method of treatment of primary bone cancer, which contemplates administering an effective amount of tin-117m stannic (Sn4+) polycarboxylate to a mammal. The pharmaceutical compositions of the present invention can also be used in a method for treatment of cancer in bone, wherein the cancer results from metastatic spread to bone from other primary cancers. Similarly, the radiopharmaceutical compositions of the present invention can also be used in a method for treatment of bone/joint disorders, such as osteoporosis, Paget""s disease, rheumatoid arthritis, osteoarthritis and the like, which includes administering an effective amount of the radiopharmaceutical composition of the present invention to a mammal. Additionally, the radiopharmaceutical composition of the present invention is also useful in a method of monitoring a skeletal system which includes administering a detectable amount of 117mSn labeled stannic (Sn4+) polycarboxylate and measuring the distribution of radioactivity throughout bony tissue and other parts of the body by applicable detection techniques.
As a result of the present invention, tin-117m stannic chelates of polyhydroxy-carboxylic acids (citrate is an example) are provided which localize almost exclusively in bone and clear rapidly from blood and other organs. Moreover, the ligands used to form tin-117m chelates provide pharmaceuticals with reduced in vivo chemical toxicity than previously developed ligands such as DTPA, PYP, MDP and EHDP.
Other improvements which the present invention provides over the prior art will be identified as a result of the following description which sets forth the preferred embodiments of the present invention. The description is not in any way intended to limit the scope of the present invention, but rather only to provide working examples of the present preferred embodiments. The scope of the present invention will be pointed out in the appended claims.